Children exposed during pregnancy to substances of abuse are also at high-risk for other environmental factors associated with early life stress (ELS). Basic and clinical research shows that these various exposures, individually or in combination, can disrupt early developmental trajectories of brain structure and function and enduring health risk for the child. This R34 HEAL planning grant application from Children?s Hospital Los Angeles (CHLA)/University of Southern California (USC) will be vital for consortium hypothesis generation in Phase II in order to disentangle how complex environmental factors impact brain development and function - from fetal period through the first decade - to shape cognitive, social and emotional development. The risk factors for families served by this campus of clinics, CHLA, Hollywood Presbyterian Hospital and Altamed Community Medical Center, is unparalleled in California. Of the families to be recruited, >75% are on Medicaid, more than 50% are below the federal poverty level, and there is enrichment of Hispanic/Latinx of any race. The USC-CHLA team of investigators and bilingual and multi-cultural research staff bring a depth of expertise in recruitment during pregnancy and early postnatal, as well as experimental expertise in epidemiology, neuroimaging, neurophysiology, developmental psychology and behavioral pediatrics, and biomeasures. To ensure maximum protection of a vulnerable population and effective recruitment and retention, the team includes a world- renowned expert in social/legal and medical ethics to complement our experience and community partnerships. For HEAL Phase I, two cohorts will be recruited to meet age range goals. Cohort 1 will include 40 pregnant women and their fetuses/infants to test the feasibility and utility of different study visit schedules on data quality and subject burden. Cohort 2 will include 10 mother-toddler dyads recruited from one of our two ongoing longitudinal studies investigating the impact of early life stress on development. Three specific aims will address the stated goals of the HEAL RFA: Aim 1) to develop the strategies to recruit and retain a racially- and ethnically diverse sample of pregnant women (and their fetuses), who are oversampled for adverse environmental risk factors and exposure to substances of abuse; Aim 2) to develop the strategies for managing potential legal and ethical challenges to ensure that the mother-child dyads have access to legal, social and psychological support services as needed; Aim 3) to determine the optimal study protocol for the planned, phase II study ? balancing the need for high quality, longitudinal data collection with the need to minimize burden on the mother-child dyads. The multidisciplinary approaches include fetal, infant and toddler MRI, high-resolution electroencephalography and eye-tracking, promising biosamples (child buccal swab, urine and blood drops; mother breastmilk, blood and hair), and demographic, physical and mental health, social support for mother/child dyads, and behavioral- cognitive measures in children. Lessons learned from recruitment, retention and data collection will be fully shared in order to form best hypotheses and research designs for the Phase II HEAL initiative.